Process for producing pyridinecarboxamides or thiocarboxamides

ABSTRACT

A process for producing N-substituted pyridine carboxamide or thiocarboxamide, comprising reacting a substituted or unsubstituted pyridine metal compound with substituted isocyanate or isothiocyanate to obtain an addition reaction product thereof, and then substituting the metal of said addition reaction product with a proton. The process according to the present invention can be applied even to compounds having an oxidation-susceptible substituent group and, therefore, industrially useful.

This application is a 371 application of PCT/JP96/03806 filed Dec. 26,1996.

TECHNICAL FIELD

The present invention relates to a process for producing N-substitutedpyridine carboxamide or thiocarboxamide, and more particularly, itrelates to an industrially useful process for producing N-substitutedpyridine carboxamide or thiocarboxamide.

BACKGROUND ART

It is known that N-substituted-6-pyridine carboxamide or thiocarboxamidehas a herbicidal activity, as described, for example, in Japanese PatentApplication Laid-open (KOKAI) No. 4-290805, U.S. Pat. No. 4,270,946 orthe like. As the most ordinary method for producing the above-mentionedcompounds, there is known a method comprising producing a carboxylicacid, halogenating the carboxylic acid and then reacting the halogenatedcarboxylic acid with amine. In the above Japanese Patent ApplicationLaid-open (KOKAI) No. 4-290805, it is described that pyridine carboxylicacid is produced by such an oxidation reaction of methyl pyridine asdescribed in "J. Pharm. Belg." (1980), 35, 1, 5-11.

However, it has been difficult to produce the pyridine carboxylic acidhaving an oxidation-susceptible substituent group bonded to a pyridinering thereof, such as an alkyl group, an amino group or a group havingthiol ether bond, by the oxidation reaction such as oxidation of amethyl group with a high yield.

In addition, there is conventionally unknown any method of producingN-substituted pyridine thiocarboxamide without sulfidization ofN-substituted pyridine carboxamide, until the process according to thepresent invention has been proposed herein by the present inventors.

The present invention has been attained in view of the above-mentionedproblems. It is an object of the present invention to provide aindustrially useful process for producing N-substituted pyridinecarboxamide or thiocarboxamide, which can reduce limitations toproduction thereof.

As a result of the present inventors' earnest studies concerning a novelprocess for the production of N-substituted pyridine carboxamide orthiocarboxamide, it has been found that by reacting a pyridine metalcompound and substituted isocyanate (or isothiocyanate) with each other,the aimed products, even N-substituted pyridine carboxamide having anoxidation-susceptible substituent group, can be produced with a highyield, and N-substituted pyridine thiocarboxamide can be produced with ahigh yield without sulfidization of N-substituted pyridine carboxamide.The present invention has been attained on the basis of the finding.

DISCLOSURE OF THE INVENTION

That is, in an aspect of the present invention, there is provided aprocess for producing N-substituted pyridine carboxamide orthiocarboxamide, comprising reacting a pyridine metal compound withsubstituted isocyanate (or thioisocyanate) to obtain an additionreaction product thereof, and then substituting the metal of theaddition reaction product with a proton.

The present invention is described in detail below. In the presentinvention, N-substituted pyridine carboxamide or thiocarboxamide can beusually produced by reacting a pyridine metal compound with asubstituted isocyanate or thioisocyanate (in the present specification,which means not only compounds expressed by the terminology "substitutedisocyanate or thioisocyanate", especially those represented herein bythe specific chemical formulae, but also compounds to which at least oneisocyanate or thioisocyanate group is bonded) to obtain an additionreaction product thereof, and then substituting the metal of theaddition reaction product with a proton. The above-mentioned pyridinemetal compound and substituted isocyanate or thioisocyanate are notlimited to particular ones as far as N-substituted pyridine carboxamideor thiocarboxamide can be produced therefrom by the process according tothe present invention.

As the substituent groups of the above-mentioned pyridine metalcompounds, there may be usually exemplified a halogen atom, an alkylgroup, a haloalkyl group, an alkoxy group, a haloalkoxy group, analkylthio group, a haloalkylthio group, a dialkylamino group, a(substituted or unsubstituted)phenoxy group, a (substituted orunsubstituted)phenylthio group, a di(substituted or unsubstitutedphenyl)amino group, an alkyl{(substituted or unsubstituted)phenyl)}aminogroup, an alkyl{(substituted or unsubstituted)phenylalkyl}amino group, a{(substituted or unsubstituted)phenyl} or {{(substituted orunsubstituted)phenyl}alkyl}amino group or the like.

As the metals of the above-mentioned pyridine metal compounds, there maybe usually exemplified alkali metals such as lithium, sodium orpotassium; alkali earth metals such as magnesium; alkali earth metalhalogen; copper alkali metal; copper alkali earth metal halogen; or thelike.

The production process according to the present invention can be shownby the following reaction formula (1).

The N-substituted pyridine carboxamide or pyridine thiocarboxamiderepresented by the formula (I) can be produced by reacting the pyridinemetal compound represented by the formula (II) with the substitutedisocyanate (or isothiocyanate) represented by the formula (III) to forma carbon-carbon bond between a carbon atom of pyridine ring and that ofthe substituted isocyanate (or isothiocyanate) and obtain an additionreaction product thereof, and then substituting the metal of theaddition reaction product with a proton.

The above-mentioned substitution of the metal with a proton may becarried out by treating the obtained addition reaction solution with anaqueous acid solution. This reaction is shown by the following reactionformula (1). ##STR1## wherein R is a hydrogen atom, a halogen atom, analkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, analkylthio group, a haloalkylthio group, a dialkylamino group, a(substituted or unsubstituted)phenoxy group, a (substituted orunsubstituted)phenylthio group, a di{(substituted orunsubstituted)phenyl}amino group, an alkyl{(substituted orunsubstituted)phenyl}amino group, an alkyl{(substituted orunsubstituted)phenylalkyl}amino group or a {(substituted orunsubstituted)phenyl} {{(substituted or unsubstituted)phenyl}alkyl}aminogroup;

m is an integer of 0 to 4, and when m is an integer of not less than 2,Rs are the same or different;

A is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkylgroup, a cycloalkylalkyl group, a phenyl group or an aralkyl group;

X is a halogen atom, an alkoxy group, a haloalkoxy group, an alkylthiogroup, an alkyl group, a haloalkyl group or a di(alkyl)amino group;

n is 0 to an integer selected from numbers of hydrogen atoms which canbe substituted with hydrocarbon groups, and when n is an integer of notless than 2, Rs may be the same or different;

Z is an oxygen atom or a sulfur atom; and

M is alkali metal, alkali earth metal-Q wherein Q is a halogen atom, or1/2(Cu-alkali metal).

Next, the definition of A used in the present specification areexplained below.

The chain-like hydrocarbon moiety of A is constituted by a longestcarbon chain as a main chain exclusive of alkyl groups bonded as sidechains to the main chain, and the alkyl groups as side chains areregarded as substituents X.

That is, in the case of alkyl groups, the longest carbon chain thereofis regarded as A, and the groups bonded thereto are regarded assubstituents. Accordingly, in the case of isopropyl group, an ethylgroup is regarded as A and a methyl group bonded to the 1-position ofthe ethyl group is regarded as a substituent. Similarly, in the case oft-butyl group, an ethyl group is regarded as A, and two methyl groupsbonded to the 1-position thereof are regarded as substituents.

In the case of alkenyl group, the carbon chain from the carbon atombonded to a nitrogen atom of 2-CZN of pyridine up to the double bondlocated at the furthest position therefrom, is regarded as A, and thealkyl groups bonded as side chains to A are regarded as substituents X.

In the case of alkynyl group, the carbon chain from the carbon atombonded to a nitrogen atom of 2-CZN of pyridine up to the triple bondlocated at the furthest position therefrom, is regarded as A, and thealkyl groups bonded as side chains to A are regarded as substituents X.

In the case where both the double and triple bonds are included in A,the carbon chain from the carbon atom bonded to a nitrogen atom of 2-CZNof pyridine up to the multiple bond located at the furthest positionfrom the 1-position thereof, is regarded as A, and the alkyl groupsbonded as side chains to A are regarded as substituents x.

In the case where A is an alkyl group, an alkoxy group, an alkylaminogroup or a dialkylamino group, the substituent group X is not bonded tothe terminal position of A.

R may include the following specific substituents:

Halogen atoms such as fluorine, chlorine, bromine or iodine;

Alkyl groups, usually C₁ to C₁₀ alkyl groups, for example, C₁ to C₄alkyl groups such as methyl, ethyl, 1-methylethyl, propyl or the like;

Haloalkyl groups, usually C₁ to C₁₀ haloalkyl groups, for example, C₁ toC₄ haloalkyl groups such as trifluoromethyl or1,1,2,2,2-pentafluoroethyl;

Alkoxy groups, usually C₁ to C₁₀ alkoxy groups, for example, C₁ to C₄alkoxy groups such as methoxy, ethoxy or propoxy;

Haloalkoxy groups, usually C₁ to C₁₀ haloalkoxy groups, for example, C₁to C₄ haloalkoxy groups such as 2,2,2-trifluoroethoxy;

Alkylthio groups, usually C₁ to C₁₀ alkylthio groups, for example, C₁ toC₄ alkylthio groups such as methylthio or ethylthio;

Haloalkylthio groups, usually C₁ to C₁₀ haloalkylthio groups, forexample, C₁ to C₄ haloalkylthio groups such as 2,2,2-trifluoroethylthio;

Dialkylamino groups, usually di(C₁ to C₁₀ alkyl)amino groups, forexample, di(C₁ to C₄ alkyl)amino groups such as dimethylamino,diethylamino or ethylmethylamino;

Phenoxy group;

Phenylthio group;

diphenylamino groups;

(Alkyl)(phenylalkyl)amino groups, usually (C₁ to C₁₀ alkyl) (phenyl C₁to C₅ alkyl)amino groups, for example, (C₁ to C₄ alkyl) (phenyl C₁ to C₃alkyl)amino groups such as methyl(phenylmethyl)amino,methyl(phenylethyl)amino or ethyl(phenylmethyl)amino;

Alkyl(phenyl)amino groups, usually (C₁ to C₄ alkyl)(phenyl)amino groups,for example, methyl(phenyl)amino, ethyl(phenyl)amino orpropyl(phenyl)amino; or

(Phenyl)(phenylalkyl)amino groups, usually (phenyl) (phenyl C₁ to C₅alkyl)amino groups, for example, phenyl(phenyl C₁ to C₃ alkyl)aminogroups such as phenyl(phenylmethyl)amino or phenyl(phenylethyl)amino.

As the substituents bonded to a benzene ring of phenyl of R, there maybe exemplified the following substituents: halogen atoms, alkyl groups,haloalkyl groups, alkoxy groups, haloalkoxy groups, alkylthio group,haloalkylthio groups, dialkylamino groups, a phenoxy group, a phenylthiogroup, a diphenylamino group, alkyl(phenyl)amino groups,alkyl(phenylalkyl)amino groups or {{substituted orunsubstituted)phenyl}alkyl}amino groups.

As the substituents bonded to a benzene ring of phenyl of R, there maybe exemplified the following substituents: halogen atoms such asfluorine, chlorine, bromine or iodine; alkyl groups, usually C₁ to C₁₀alkyl groups; haloalkyl groups, usually C₁ to C₁₀ haloalkyl groups;alkoxy groups, usually C₁ to C₁₀ alkoxy groups; haloalkoxy groups,usually C₁ to C₁₀ haloalkoxy groups; alkylthio group, usually C₁ to C₁₀alkylthio groups; haloalkylthio groups, usually C₁ to C₁₀ haloalkylthiogroups; dialkylamino groups, usually di(C₁ to C₁₀ alkyl)amino groups; aphenoxy group; a phenylthio group; a diphenylamino group;alkyl(phenyl)amino groups, usually (C₁ to C₁₀ alkyl)(phenyl)aminogroups; alkyl(phenylalkyl)amino groups, usually (C₁ to C₁₀ alkyl)(phenyl C₁ to C₅ alkyl)amino groups; or phenyl(phenylalkyl)amino groups,usually (phenyl)(phenyl C₁ to C₅ alkyl)amino groups.

As the preferred substituents bonded to the phenyl of R, there may berespectively exemplified: as the halogen atoms, fluorine, chlorine orbromine; as the alkyl groups, C₁ to C₄ alkyl groups, for example,methyl, ethyl or propyl; as the haloalkyl groups, C₁ to C₄ haloalkylgroups, for example, trifluoromethyl or 1,1,2,2,2-pentafluoroethyl; asthe alkoxy groups, C₁ to C₄ alkoxy groups, for example, methoxy, ethoxyor propoxy; as the haloalkoxy groups, C₁ to C₄ haloalkoxy groups, forexample, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy or2,2,3,3,3-pentafluoropropoxy; as the alkylthio groups, C₁ to C₄alkylthio groups, for example, methylthio or ethylthio; as thehaloalkylthio groups, C₁ to C₄ haloalkylthio groups, for example,trifluoromethylthio; as the dialkylamino groups, di(C₁ to C₄ alkyl)aminogroups, for example, dimethylamino, diethylamino or ethylmethylamino; aphenyl group; a phenoxy group; a phenylthio group; a diphenylaminogroup; as the (alkyl)(phenyl)amino groups, (C₁ to C₄ alkyl)(phenyl)aminogroups, for example, methylphenylamino, ethylphenylamino orpropylphenylamino; as the (alkyl) (phenylalkyl)amino groups, (C₁ to C₄alkyl) (phenyl C₁ to C₃ alkyl)amino groups, for example,methyl(phenylmethyl)amino, methyl(phenylethyl)amino orethyl(phenylmethyl)amino; and as the (phenyl)(phenylalkyl)amino groups,(phenyl)(phenyl C₁ to C₃ alkyl)amino groups, for example,phenyl(phenylmethyl)amino or phenyl(phenylethyl)amino. phenyl(C₁ to C₃alkyl) groups (indicating such arylalkyl groups whose alkyl moiety has 1to 3 carbon atoms and whose aryl group is phenyl) such as phenylmethyl,phenylethyl, phenylpropyl or the like;

As the more preferred substituents bonded to the phenyl of R, there maybe respectively exemplified: as the halogen atoms, fluorine or chlorine;as the alkyl groups, C₁ to C₄ alkyl groups, for example, methyl, ethylor propyl; as the haloalkyl groups, C₁ to C₄ haloalkyl groups, forexample, trifluoromethyl; as the alkoxy groups, C₁ to C₄ alkoxy groups,for example, methoxy or ethoxy; as the haloalkoxy groups, C₁ to C₄haloalkoxy groups, for example, trifluoromethoxy or difluoromethoxy; asthe alkylthio groups, C₁ to C₄ alkylthio groups, for example, methylthioor ethylthio; as the haloalkylthio groups, C₁ to C₄ haloalkylthiogroups, for example, trifluoromethylthio; and as the dialkylaminogroups, di(C₁ to C₄ alkyl)amino groups, for example, dimethylamino ordiethylamino.

As the substituents A, there may be respectively exemplified: as alkylgroups, usually C₁ to C₁₀ alkyl groups; as alkenyl groups, usually C₃ toC₁₀ alkenyl groups; as alkynyl groups, usually C₃ to C₁₀ alkynyl groups;as cycloalkyl groups, usually C₃ to C₁₂ cycloalkyl groups; ascycloalkylalkyl groups, usually (C₃ to C₁₂ cycloalkyl) (C₁ to C₅ alkyl)groups; a phenyl group; and as phenylalkyl groups, phenyl C₁ to C₅ alkylgroups.

As the preferred substituents A, there may be respectively exemplified:as the alkyl groups, C₁ to C₈ alkyl groups, for example, methyl, ethyl,propyl, butyl or pentyl; as the alkenyl groups, C₃ to C₆ alkenyl groups,for example, 2-propenyl; as the alkynyl groups, C₃ to C₆ alkynyl groups,for example, 2-propynyl; as the cycloalkyl groups, C₃ to C₆ cycloalkylgroups, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;as the cycloalkylalkyl groups, (C₃ to C₈ cycloalkyl) (C₁ to C₃ alkyl)groups, for example, cyclopropylmethyl or cyclohexylmethyl; a phenylgroup; and as the phenylalkyl groups, phenyl C₁ to C₃ alkyl groups, forexample, phenylmethyl or phenylethyl.

As the substituents X, there may be exemplified halogen atoms, usuallyC₁ to C₆ alkoxy groups, usually C₁ to C₆ haloalkoxy groups, usually C₁to C₆ alkylthio groups, usually C₁ to C₆ alkyl groups, usually C₁ to C₆haloalkyl groups or usually di(C₁ to C₆ alkyl)amino groups.

As the preferred substituents X, there may be respectively exemplified:as the halogen atoms, fluorine, chlorine or bromine; as the C₁ to C₄alkoxy groups, methoxy, ethoxy or propoxy; as the C₁ to C₄ haloalkoxygroups, trifluoromethoxy, difluoromethoxy or 2,2,2-trifluoroethoxy; asthe C₁ to C₄ alkylthio groups, methylthio or ethylthio; as the C₁ to C₄alkyl groups, methyl, ethyl or propyl; as the C₁ to C₄ haloalkyl groups,trifluoromethyl; and as the di(C₁ to C₄ alkyl)amino groups,dimethylamino or diethylamino.

As the more preferred substituents X, there may be respectivelyexemplified: as the halogen atoms, fluorine or chlorine; as the C₁ to C₄alkoxy groups, methoxy, ethoxy or propoxy; as the C₁ to C₄ haloalkoxygroups, trifluoromethoxy; as the C₁ to C₄ alkylthio groups, methylthioor ethylthio; as the C₁ to C₄ alkyl groups, methyl, ethyl or propyl; andas the C₁ to C₄ haloalkyl groups, trifluoromethyl.

The integer n represents 0 to an integer selected from numbers ofhydrogen atoms which can be substituted with hydrocarbon groups,preferably 0 (indicating unsubstituted condition) to 7. In the casewhere n is an integer of not less than 2, Xs may be the same ordifferent.

The above-mentioned compound (II) can be readily produced by the methoddescribed hereinafter.

Further, as the substituted isocyanate or isothiocyanate (III) in thepresent invention, there may be used commercially available products orthose produced in the following manner.

For example, there may be used substituted isocyanates which can beproduced by reacting a primary amine with phosgene or oxalyl dichloride,or substituted thioisocyanates which can be produced by reacting theprimary amine with thiophosgene or carbon disulfide. Examples of theprimary amines may include alkyl amines such as methyl amine or ethylamine; alkenyl amines such as allyl amine; alkynyl amines such aspropargyl amine; cycloalkyl amines such as cyclopropyl amine, cyclobutylamine or cyclohexyl amine; haloalkyl amines such as 2,2,2-trifluoroethylamine, 2,2,3,3,3-pentafluoropropyl amine, 2-chloroethyl amine,2-bromoethyl amine or 3-chloropropyl amine; alkoxyalkyl amines such as2-(ethoxy)ethyl amine or 3-(methoxy)propyl amine; alkylthioalkyl aminessuch as 2-(ethylthio)ethyl amine or 3-(methylthio)propyl amine; aniline;halogen-substituted anilines such as 2-chloroaniline or 4-bromoaniline;alkyl-substituted anilines such as 4-methyl aniline or 4-ethyl aniline;alkoxy-substituted anilines such as 4-methoxy aniline or 3-ethoxyaniline; alkylthio-substituted anilines such as 4-(methylthio) anilineor 3-(methylthio) aniline; haloalkyl-substituted anilines such as3-(trifluoromethyl) aniline or 4-(trifluoromethyl) aniline;haloalkoxy-substituted anilines such as 3-(trifluoromethoxy) aniline or4-(trifluoromethoxy) aniline; phenylalkyl amines such as benzyl amine;or the like.

In addition, there may be used substituted isocyanates which can beproduced by reacting halides (for example, alkyl halides such as methyliodide or propyl iodide; alkenyl halides such as allyl iodide or2-(methyl)allyl chloride; alkynyl halides such as propargyl bromide;alkoxyalkyl halides such as 2-(ethoxy)ethyl chloride; alkylthioalkylhalides such as (methylthio)methyl chloride; or the like) with cyanates,or substituted thioisocyanates which can be produced by the reactionbetween the halides and thiocyanates, or the like.

Examples of the substituted isocyanates or thioisocyanates areenumerated in Table 1 below.

                  TABLE 1                                                         ______________________________________                                        (1/2)                                                                         ______________________________________                                             phenyl isocyanate; phenyl isothiocyanate; benzyl isocyanate;                   cyclohexyl isocyanate; 4-chlorophenyl isocyanate; 3-                      chlorophenyl isocyanate; 2-chlorophenyl isocyanate; 4-                        methylphenyl isocyanate; 3-methylphenyl isocyanate; 2-                        methylphenyl isocyanate; 4-methoxyphenyl isocyanate; 2-                       ethoxyphenyl isocyanate; 4-ethoxyphenyl isocyanate; 4-                        bromophenyl isocyanate; 4-(methylthio)phenyl isocyanate; 3-                   (trifluoromethyl)phenyl isocyanate; 4-fluorophenyl isocyanate;                3-fluorophenyl isocyanate; 2-fluorophenyl isocyanate; 2,4-                    difluorophenyl isocyanate; allyl isocyanate                                 ______________________________________                                              (2/2)                                                                   ______________________________________                                                     methyl isocyanate; ethyl isothiocyanate; 2-chloroethyl                         isocyanate; n-propyl isocyanate; n-propyl isothiocyanate;                    i-                                                                 propyl isocyanate; t-butyl isocyanate; n-butyl isocyanate; n-                 butyl isothiocyanate                                                        ______________________________________                                    

In the addition reaction for producing the present compound (I), theamount of the compound (III) used is usually 0.5 to 5.0 moles,preferably 1.0 to 2.5 moles based on one mole of the compound (II). Thereaction temperature is usually -100 to 150° C., preferably -80 to 80°C.

The solvents used in the above addition reaction are those preferablefor carrying out the reaction of isocyanate. As such solvents, there maybe usually exemplified aliphatic hydrocarbons such as petroleum ethers,pentane, hexane, heptane or methylcyclohexane; ethers such as diethylether, dimethoxy ethane, diisopropyl ether, tetrahydrofuran, diethyleneglycol dimethyl ether or dioxane; or aromatic hydrocarbons such asbenzene, toluene, xylene or methylnaphthalene. These solvents may beused in the form of a mixture of any two or more thereof.

As the acids used in the above-mentioned substitution of the metal withproton, there may be usually exemplified inorganic acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid orsulfuric acid; organic acids such as formic acid, acetic acid, butyricacid or p-toluene sulfonic acid; or the like. These acids may be used inthe form of a mixture of any two or more thereof.

The present compound (I) obtained in the above-mentioned reaction may beseparated by ordinary separation methods. For example, the reactionmixture is extracted with an organic solvent, and the solvent isdistilled off to obtain a residue. The obtained residue is separatedinto fractions by column chromatography, and the resultant separatedsolution is concentrated and treated with poor solvent such as hexane toobtain a precipitate. If required, the precipitate may be furtherpurified by recrystallization.

As the solvents used in the above separation process, there may beusually exemplified aromatic hydrocarbons such as benzene, toluene,xylene or methylnaphthalene; aliphatic hydrocarbons such as petroleumethers, pentane, hexane, heptane or methylcyclohexane; halogenatedhydrocarbons such as methylene chloride, chloroform, carbontetrachloride or chlorobenzene; amides such as dimethyl formamide,dimethyl acetamide or N-methyl-2-pyrrolidinone; ethers such as diethylether, dimethoxy ethane, diisopropyl ether, tetrahydrofuran, diethyleneglycol dimethyl ether or dioxane; or the like. As other usable solvents,there may be exemplified water, carbon disulfide, acetonitrile, ethylacetate, dimethyl sulfoxide, hexamethylphosphoric triamide or the like.These solvents can be used in the form of a mixture of any two or morethereof.

The above-mentioned compound (II) may be produced by metalation of thecompound (IV), as shown in the following reaction formula. Asmetallizing reagents for carrying out the metalation, there may be usedthose preferable for the metalation. As such metallizing reagents, theremay be usually exemplified organic alkali metal compounds such as butyllithium, sec-butyl lithium, tert-butyl lithium, methyl lithium or phenyllithium; alkali metal amides such as lithium diisopropyl amide; alkalimetals such as lithium, sodium or potassium; alkali earth metals such asmagnesium; copper alkali metal; copper alkali earth metal halogen; orthe like.

As the pyridine metal compound (II), there may be used, for example, acopper-containing compound (corresponding to the compound (II) wherein Mis 1/2(Cu-alkali metal) or 1/2(Cu-alkali earth metal halogen)) preparedby reacting a compound of alkali metal such as lithium, sodium orpotassium, preferably lithium (corresponding to the compound (II)wherein M is alkali metal, preferably lithium) or a Grignardreagent-type compound (corresponding to the compound (II) wherein M isalkali earth metal halogen) with a monovalent-copper salt such as copperiodide (CuI). This reaction is shown by the following reaction formula(2). ##STR2## wherein R, M and m are the same as defined hereinbeforewith respect to the reaction formula (1), and T represents an atom to besubstituted, a halogen atom or a hydrogen atom, which may be bonded toany position of pyridine ring.

The amount of the metallizing reagent used is usually 0.5 to 5.0 moles,preferably 0.8 to 2.0 moles based on one mole of the compound (IV). Thereaction temperature is usually -100° C. to 150° C., preferably -80° C.to 80° C.

The solvents used in the above-mentioned reaction may include thosepreferable for the production of organic metal compounds. As suchsolvents, there may be usually exemplified aliphatic hydrocarbons suchas petroleum ethers, pentane, hexane, heptane or methylcyclohexane;ethers such as diethyl ether, dimethoxy ethane, diisopropyl ether,tetrahydrofuran, diethylene glycol dimethyl ether or dioxane; aromatichydrocarbons such as benzene, toluene, xylene or methylnaphthalene; orthe like. These solvents can be used in the form of a mixture of any twoor more thereof.

The thus obtained reaction solution was subjected to the next additionreaction usually without separation of the compound (II). Therefore, thesolvent used in the metalation can be used as a solvent for the nextaddition reaction as it is.

At this time, for example, when M is lithium, different kinds ofpyridine metal compounds (II) which are metallized at differentpositions of the pyridine ring, can be produced by selectively using thecompound (IV) to be metalated and the metallizing reagent. Some examplesare described below.

In the case of monohalogenopyridine compounds:

When 2-bromopyridine is treated with LDA (lithium diisopropyl amide) inTHF (tetrahydrofuran) at -78° C., the hydrogen atom bonded to the3-position of the pyridine ring is substituted with lithium. On theother hand, when 2-bromopyridine is treated with n-butyl lithium, thebromine atom bonded to the 2-position thereof is substituted withlithium (refer to "Synthesis", 235, 237 (1982)).

When 2-fluoropyridine is treated with LDA in THF at -70° C., thehydrogen atom bonded to the 3-position of the pyridine ring issubstituted with lithium (refer to "J. Org. Chem.", 47, 2633 (1982)). Onthe other hand, when 2-fluoropyridine is treated with n-butyl lithium,an addition reaction product thereof is obtained (refer to"Tetrahedron", 39, 2009 (1983)).

When 3-fluoropyridine is treated with n-butyl lithium in THF and TMEDA(tetramethyl ethylenediamine) at -40° C., the hydrogen atom bonded tothe 4-position of the pyridine ring is substituted. On the other hand,when diethyl ether is used instead of THF, the hydrogen atom bonded tothe 2-position thereof is substituted (refer to "Tetrahedron", 39, 2009(1983)).

When 3-chloropyridine is treated with LDA in THF at -60° C., thehydrogen atom bonded to the 4-position of the pyridine ring issubstituted (refer to "J. Org. Chem.", 47, 2633 (1982)).

When 4-chloropyridine is treated with LDA in THF at -40° C., thehydrogen atom bonded to the 3-position of the pyridine ring issubstituted with lithium (refer to "J. Org. Chem.", 47, 2633(1982)).

In the case of dihalogenopyridines:

When 2,4-dibromopyridine is treated with n-butyl lithium in THF, thebromine atom bonded to the 4-position of the pyridine ring issubstituted with lithium (refer to "Thesis, Univ. Antwerp." (1988)).

When 2,5-dibromopyridine is treated with n-butyl lithium in THF, thebromine atom bonded to the 5-position of the pyridine ring issubstituted with lithium (refer to "Thesis, Univ. Antwerp." (1988)).

When 2,6-dibromopyridine is treated with n-butyl lithium in diethylether, one of the bromine atoms is substituted with lithium (refer to"Chem. Pharm. Bull.", 36, 634 (1988)).

When 3,5-dibromopyridine is treated with n-butyl lithium in diethylether, one of the bromine atoms is substituted with lithium (refer to"J. Org. Chem.", 16, 1485 (1988)).

In the case of alkoxypyridines:

When 2-methoxypyridine is treated with LDA, the hydrogen atom bonded tothe 3-position of the pyridine ring is substituted with lithium (referto "J. Org. Chem.", 53, 1367 (1988)).

When 3-ethoxypyridine is treated with n-butyl lithium in diethyl etherand TMEDA, the hydrogen atom bonded to the 4-position of the pyridinering is substituted with lithium (refer to "Synthesis", 235, 237(1982)).

Thus, when the compound (IV) is treated under the above-mentionedvarious production conditions for selective lithium-substitution(lithiation), it is possible to produce such a compound which issubstituted with lithium (lithiated) at a required position of thepyridine ring (i.e., compound (II) wherein M is lithium). Accordingly,when the compound (II) wherein M is lithium, is reacted with thecompound (III), it is possible to produce the compound (I) to which anN-substituted carbamoyl group or an N-substituted thiocarbamoyl group isbonded at a required position of pyridine ring thereof.

The compound (II) wherein M is magnesium, may be produced by convertingthe halogen atom bonded to the pyridine ring of the compound (IV) to aGrignard reagent.

The organic copper compound may be produced by the metal-metal exchangereaction between the above-produced organic lithium compound or organicmagnesium compound in which lithium or magnesium is bonded to thepyridine ring thereof, and a copper salt.

Further, the compound (IV) used in the process according to the presentinvention may be produced in the following manner.

First, in the case of halogen-substituted pyridines, as the preferredhalogen atoms, there may be exemplified a fluorine atom, a chlorineatom, a bromine atom or an iodine atom. Among these compounds, forexample, as monohalogenopyridines (2-fluoropyridine, 3-fluoropyridine,2-chloropyridine, 3-chloropyridine, 4-chloropyridine, 2-bromopyridine,3-bromopyridine, 4-bromopyridine, 2-chloro-6-trifluoromethyl pyridine,6-chloro-2-picoline or the like), and dihalogenopyridines(2,3-dichloropyridine, 2,5-dichloropyridine, 2,6-dichloropyridine,3,5-dichloropyridine, 2,5-dibromopyridine, 2,6-dibromopyridine,3,5-dibromopyridine, 2,6-dichloro-3-nitropyridine,2,6-dichloro-3-trifluoromethyl pyridine, 2,6-dichloro-4-trifluoromethylpyridine or the like), there may be used commercially availableproducts. In addition, 2,6-dibromo-4-methyl pyridine can be produced bysubstituting a hydroxyl group of 2-bromo-6-hydroxy-4-methyl pyridinewith a halogen atom, as described in Japanese Patent ApplicationLaid-open (KOKAI) No. 6-40813. Also, for example, 2-bromo-4-methylpyridine or 2-bromo-6-methyl pyridine can be produced by substituting ahydroxyl group of 2-hydroxy-4-methyl pyridine or 2-hydroxy-6-methylpyridine with a halogen atom. Further, among these compounds, withrespect to such compounds having a halogen atom bonded to the 2- or4-position of the pyridine ring, by subjecting (substituted orunsubstituted) alcohols, (substituted or unsubstituted) alkylthiols,(substituted or unsubstituted) alkylamines, di(substituted orunsubstituted) alkylamines, (substituted or unsubstituted) phenols,(substituted or unsubstituted) thiophenols, (substituted orunsubstituted) aniline, di(substituted or unsubstituted)phenyl amines or(substituted or unsubstituted)phenylalkyl amines, to nucleophilichalogen-substitution reaction under basic conditions, there may beproduced corresponding halogen-substituted alkoxy compounds, alkylthiocompounds, alkylamino compounds, dialkylamino compounds, (substituted orunsubstituted)phenoxy compounds, (substituted orunsubstituted)phenylthio compounds, (substituted orunsubstituted)phenylamino compounds, di(substituted orunsubstituted)phenylamino compounds or (substituted orunsubstituted)phenylalkylamino compounds. Also, with respect to suchcompounds having a nitro group bonded to the 2- or 4-position of thepyridine ring (among them, for example, 2-nitropyridine has beendescribed in "Ber.", 64, 767 (1931); and 2,6-dichloro-4-nitropyridinehas been described in Japanese Patent Application Laid-open (KOKAI) No.57-126474 (1982) in which the production of 2,6-dibromo-4-nitropyridineor the like have also been described), by subjecting (substituted orunsubstituted) alcohols, (substituted or unsubstituted) alkylthiols,(substituted or unsubstituted)alkyl amines, di(substituted orunsubstituted)alkyl amines, (substituted or unsubstituted) phenols,(substituted or unsubstituted) thiophenols, (substituted orunsubstituted) anilines, di(substituted or unsubstituted)phenyl aminesor (substituted or unsubstituted)phenylalkyl amines, to nucleophilicnitro-substitution reaction under basic conditions, there may beproduced corresponding nitro-substituted (substituted orunsubstituted)alkoxy compounds, (substituted or unsubstituted)alkylthiocompounds, (substituted or unsubstituted)alkylamino compounds,di(substituted or unsubstituted)alkylamino compounds, (substituted orunsubstituted) phenoxy compounds, (substituted orunsubstituted)phenylthio compounds, (substituted orunsubstituted)phenylamino compounds, di(substituted orunsubstituted)phenylamino compounds or (substituted orunsubstituted)phenylalkylamino compounds. Furthermore, by conductingnucleophilic substitution reaction between compounds having a hydroxylgroup, a thiol group or an amino group on the pyridine ring thereof,such as pyridinol compounds (including commercially available productssuch as 2-pyridinol, 3-pyridinol, 4-pyridinol, 2-bromo-3-pyridinol,5-chloro-2-pyridinol, 2-chloro-3-pyridinol, 5-chloro-2-pyridinol,6-chloro-2-pyridinol or the like, or those produced by hydrolysis ofnitro compounds, hydrolysis of halogen compounds, diazotation of aminocompounds followed by hydrolysis thereof, or the like), pyridine thiolcompounds (which can be produced by thiol-substitution of nitrocompounds or halogen compounds, or the like) or aminopyridine compounds(including commercially available products such as 2-aminopyridine,3-aminopyridine or 4-aminopyridine, or those produced by reduction ofnitro compounds such as 2-chloro-3-nitropyridine or2,6-dichloro-3-nitropyridine or by the substitution reaction between theabove-mentioned halogen atoms or nitrocompounds and amino compounds, orthe like), and (substituted or unsubstituted)alkyl halides or(substituted or unsubstituted)phenylalkyl halides under basicconditions, there may be produced corresponding (substituted orunsubstituted)alkoxy compounds, (substituted or unsubstituted)alkylthiocompounds, (substituted or unsubstituted)alkylamino compounds,di(substituted or unsubstituted)alkylamino compounds, (substituted orunsubstituted)alkyl{(substituted or unsubstituted) phenyl}aminocompounds, (substituted or unsubstituted)alkyl{(substituted orunsubstituted) phenylalkyl}amino compounds or {(substituted orunsubstituted)phenyl}{(substituted or unsubstituted) phenylalkyl}aminocompounds.

The process for the production of such compounds (IV) having substituentgroups on the 2-, 4- and 6-positions of the pyridine ring thereof, isshown by the following reaction formula (3). ##STR3## wherein R¹ is analkoxy group, an alkylthio group or a (substituted orunsubstituted)phenoxy group, and R¹ s may be the same or different; R²is an alkyl group; R³ is an alkyl group or a phenylalkyl group; T¹, T²and T³ are a halogen atom and may be the same or different in which thehalogen atom represents a fluorine atom, a chlorine atom, a bromine atomor an iodine atom.

As shown in the reaction formula (3), the compound (VIII) can beproduced by nucleophilically substituting the nitro group of thecompound (V) with R² --NH₂ {(substituted or unsubstituted)alkyl amine}under basic conditions (in the case of alkylamine or the like, the useof base is occasionally unnecessary since these compounds themselvesexhibit a high nucleophilic property).

The compound (IX) can be produced by subjecting the compound (VIII) andR³ --X {alkyl halide or (substituted or unsubstituted)phenylalkylhalide} to nucleophilic substitution reaction under basic conditions.

The compounds (VI), (VII) and (X) can be produced by subjecting thecompound (V) or the compound (IX) and R¹ --H (alkanol, alkylthiol or(substituted or unsubstituted) phenol) to nucleophilic substitutionreaction under basic conditions.

As these alkyl halides, (substituted or unsubstituted)phenylalkylhalides, alkanols, alkylthiols, alkylamines or (substituted orunsubstituted) phenols, there may be used commercially availableproducts or those produced by known techniques. For example, as the(substituted or unsubstituted) phenols, the following compounds may beexemplified:

Phenol;

Halogen-substituted phenols such as 2-chlorophenol, 3-chlorophenol or4-chlorophenol;

Alkyl-substituted phenols such as 3-methylphenol;

Alkoxy-substituted phenols such as 3-methoxyphenol;

Alkylthio-substituted phenols such as 3-(methylthio) phenol;

Haloalkyl-substituted phenols such as 3-(trifluoromethyl)phenol;

Haloalkoxy-substituted phenols such as 3-(trifluoromethoxy)phenol or3-(difluoromethoxy)phenol;

Haloalkylthio-substituted phenols such as 3-(trifluoromethylthio)phenol;or

Dialkylamino-substituted phenols such as 3-(dimethylamino)phenol.

Thus, the process for producing N-substituted pyridine carboxamide orthiocarboxamide according to the present invention can be applied toeven such compounds having an oxidation-susceptible substituent group.Further, in the production process according to the present invention,N-substituted pyridine thiocarboxamide can be produced withoutsulfidization of corresponding N-substituted pyridine carboxamide.Accordingly, the process of the present invention is industriallyuseful.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in more detail below by examples, butthese examples are not intended to limit the scope of the presentinvention.

Production Example 1

Production of N-(i-propyl)-4-pyridine carboxamide (compound No. I-1)

1.0 g (0.0051 mol) of 4-bromopyridine hydrochloride was suspended inabout 30 ml of diethyl ether. While cooling the suspension in a dryice-acetone bath in an argon atmosphere, 6.6 ml of about 1.65M hexanesolution of n-butyl lithium (hereinafter referred to merely as "BuLi")(0.0051×2.1 mol) was added to the suspension, followed by stirring forabout 10 minutes. After 1.13 g (0.0067×2.0 mol) of isopropyl isocyanatedissolved in about 10 ml of diethyl ether was added to the reactionsolution, the bath was removed and stirred at room temperature for aboutone hour. The reaction solution was mixed with about 10 ml of 1Nhydrochloric acid aqueous solution, and then distributed with ethylacetate-saturated sodium bicarbonate water, followed by washing withsaturated brine. The organic phase of the obtained solution was driedwith anhydrous sodium sulfate, concentrated and purified by silica gelcolumn chromatography (eluting solution: ethyl acetate/hexane), therebyobtaining an aimed product.

Yield by weight: 0.23 g; yield by percentage: 27%; solid; melting point:105 to 107° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 1.23 (6H, d, J=6.4 Hz),3.7-4.6 (1H, mult.), 6.7-7.4 (1H, br), 7.4-7.8 (2H, complex), 8.4-8.8(2H, complex).

Production Example 2

Production of N-(i-propyl)-4-methyl-2-pyridine carboxamide (compound No.I-3)

(1) Production of 2-bromo-4-methyl pyridine as an intermediate product

4.93 g (0.045 mol) of 2-hydroxy-4-methyl pyridine was mixed with 50 mlof bromoform and then with 14.2 g (0.045×1.2 mol) of phosphorustribromide, followed by treating the mixture under reflux for about 3hours. The obtained reaction solution was concentrated and then mixedwith water. After stirring for a while, the reaction solution wasdistributed with ethyl acetate-water, followed by washing with saturatedsodium bicarbonate water and saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate. The resultantsolution was concentrated and then purified by silica gel columnchromatography (eluting solution: ethyl acetate/hexane), therebyobtaining an aimed product.

Yield by weight: 1.17 g; yield by percentage: 15%; oily substance; ¹H-NMR (60 MHz, CDCl₃, δ): 2.27 (3H, s), 7.00 (1H, d, J=6 Hz), 7.23 (1H,s), 8.17 (1H, d, J=6 Hz).

(2) Production of N-(i-propyl)-4-methyl-2-pyridine carboxamide (compoundNo. I-3)

1.0 g (0.0058 mol) of 2-bromo-4-methyl pyridine was dissolved in about30 ml of diethyl ether. While cooling the solution in a dry ice-acetonebath in an argon atmosphere, 3.9 ml of about 1.65M hexane solution ofBuLi (0.0058×1.1 mol) was added to the solution, followed by stirringthe mixture for about 10 minutes. After 1.0 g (0.0058×2.0 mol) ofisopropyl isocyanate dissolved in about 10 ml of diethyl ether was addedto the reaction solution, the bath was removed and stirred at roomtemperature for about one hour. The reaction solution was mixed withabout 10 ml of 1N hydrochloric acid aqueous solution, and thendistributed with ethyl acetate-saturated sodium bicarbonate water,followed by washing with saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate, concentratedand purified by silica gel column chromatography (eluting solution:ethyl acetate/hexane), thereby obtaining an aimed product.

Yield by weight: 0.78 g; yield by percentage: 82%; oily substance; ¹H-NMR (60 MHz, CDCl₃, δ): 1.25 (6H, d, J=6.4 Hz), 2.36 (3H, s), 3.7-4.6(1H, mult.), 7.14 (1H, d, J=6 Hz), 7.5-8.2 (1H, br), 7.94 (1H, s), 8.31(1H, d, J=6 Hz).

Production Example 3

Production of N-(i-propyl)-4-chloro-3-pyridine carboxamide (compound No.I-4)

1.0 g (0.0067 mol) of 4-chloropyridine hydrochloride was suspended inabout 30 ml of tetrahydrofuran. While cooling the suspension in a dryice-acetone bath in an argon atmosphere, 7.0 ml of about 2.0Mheptane/tetrahydrofuran/ethyl benzene solution of lithium diisopropylamide (0.0067×2.1 mol) was added to the suspension, followed by stirringfor about 10 minutes. After 1.13 g (0.0067×2.0 mol) of isopropylisocyanate dissolved in about 10 ml of tetrahydrofuran was added to thereaction solution, the solution was removed from the bath and stirred atroom temperature for about one hour. The reaction solution was mixedwith about 10 ml of 1N hydrochloric acid aqueous solution, and thendistributed with ethyl acetate-saturated sodium bicarbonate water,followed by washing with saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate, concentratedand purified by silica gel column chromatography (eluting solution:ethyl acetate/hexane), thereby obtaining an aimed product.

Yield by weight: 0.52 g; yield by percentage: 39%; solid; melting point:96 to 98° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 1.17 (6H, d, J=7 Hz), 4.14(1H, oct., J=7 Hz), 6.4-7.1 (1H, br), 7.18 (1H, d, J=5.6 Hz), 8.31 (1H,d, J=5.6 Hz), 8.49 (1H, s).

Production Example 4

Production of N-(4-methylphenyl)-6-bromo-4-methoxy-2-pyridinecarboxamide (compound No. I-7)

(1) Production of 2,6-dibromo-4-methoxy pyridine as an intermediateproduct

1.49 g (ca. 60% in mineral oil; 0.0355×1.05 mol) of sodium hydride waswashed with hexane and suspended in tetrahydrofuran. The suspension wasmixed with 1.70 g (0.0355×1.5 mol) of methanol and then with 10.00 g(0.0355 mol) of 2,6-dibromo-4-nitropyridine, and stirred at roomtemperature for about one hour. Further, the suspension was mixed with0.2 g (ca. 60% in mineral oil; 0.0355×0.14 mol) of sodium hydride, andstirred for about one hour. Next, 1.0 g (0.0355×0.9 mol) of methanol wasadded to the suspension, and after it was determined that no foaming wascaused therein, the reaction solution was distributed with ethylacetate-saturated sodium bicarbonate water. The organic phase of theobtained reaction solution was washed with saturated brine, dried withanhydrous sodium sulfate and then concentrated, thereby obtaining anaimed product.

Yield by weight: 9.27 g; yield by percentage: 98%; solid; melting point:131 to 133° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 3.79 (3H, s), 6.89 (2H, s).

(2) Production of N-(4-methylphenyl)-6-bromo-4-methoxy-2-pyridinecarboxamide (compound No. I-7)

2.0 g (0.0075 mol) of 2,6-dibromo-4-methoxy pyridine was added to about30 ml of diethyl ether. While cooling the obtained solution in a dryice-acetone bath in an argon atmosphere, the solution was mixed with 6.0ml of about 1.6M hexane solution of BuLi (0.0075×1.3 mol), followed bystirring for about 10 minutes. After 2.0 g (0.0075×2.0 mol) of4-methylphenyl isocyanate dissolved in about 5 ml of diethyl ether wasadded to the reaction solution, the bath was removed and stirred at roomtemperature for about 40 minutes. The reaction solution was mixed withabout 10 ml of 1.2N hydrochloric acid aqueous solution, and thendistributed with ethyl acetate-saturated sodium bicarbonate water,followed by washing with saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate, concentratedand subjected to silica gel column chromatography (eluting solution:ethyl acetate/hexane) to separate a main fraction therefrom. Thefraction was concentrated and then subjected to precipitation usinghexane, thereby obtaining an aimed product.

Yield by weight: 1.38 g; yield by percentage: 57%; solid; melting point:153 to 157° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 2.28 (3H, s), 3.82 (3H, s),7.02 (1H, d, J=2 Hz), 7.09 (2H, d, J=8 Hz), 7.56 (2H, d, J=8 Hz), 7.68(1H, d, J=2 Hz), 9.53 (1H, s).

Production Example 5

Production of N-benzyl-6-bromo-4-methoxy-2-pyridine carboxamide(compound No. I-9)

1.0 g (0.0037 mol) of 2,6-dibromo-4-methoxy pyridine was suspended inabout 15 ml of diethyl ether. While cooling the suspension in a dryice-acetone bath in an argon atmosphere, 2.6 ml of about 1.6M hexanesolution of BuLi (0.0037×1.1 mol) was added to the suspension, followedby stirring for about 10 minutes. After 0.75 g (0.0037×1.5 mol) ofbenzyl isocyanate dissolved in about 5 ml of diethyl ether was added tothe reaction solution, the bath was removed and stirred at roomtemperature for about 40 minutes. The reaction solution was mixed withabout 5 ml of 1N hydrochloric acid aqueous solution, and thendistributed with ethyl acetate-saturated sodium bicarbonate water,followed by washing with saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate, concentratedand purified by silica gel column chromatography (eluting solution:ethyl acetate/hexane), thereby obtaining an aimed product.

Yield by weight: 1.04 g; yield by percentage: 86%; solid; melting point:107 to 111° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 3.75 (3H, s), 4.52 (2H, d,J=6 Hz), 6.94 (1H, d, J=2 Hz), 7.20 (5H, s), 7.59 (1H, d, J=2 Hz),7.8-8.4 (1H, br).

Production Example 6

Production of N-(i-propyl)-6-bromo-4-methoxy-2-pyridine carboxamide(compound No. I-10)

1.0 g (0.0037 mol) of 2,6-dibromo-4-methoxy pyridine was suspended inabout 15 ml of diethyl ether. While cooling the suspension in a dryice-acetone bath in an argon atmosphere, 2.6 ml of about 1.6M hexanesolution of BuLi (0.0037×1.1 mol) was added to the suspension, followedby stirring for about 10 minutes. After 0.64 g (0.0037×2.0 mol) ofi-propyl isocyanate dissolved in about 5 ml of diethyl ether was addedto the reaction solution, the bath was removed and stirred at roomtemperature for about 40 minutes. The reaction solution was mixed withabout 5 ml of 1N hydrochloric acid aqueous solution, and thendistributed with ethyl acetate-saturated sodium bicarbonate water,followed by washing with saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate, concentratedand purified by silica gel column chromatography (eluting solution:ethyl acetate/hexane), thereby obtaining an aimed product.

Yield by weight: 0.76 g; yield by percentage: 74%; solid; melting point:70 to 76° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 1.25 (6H, d, J=6.4 Hz), 3.82(3H, s), 3.8-4.6 (1H, mult.), 6.98 (1H, d, J=2 Hz), 7.0-7.9 (1H, br),7.61 (1H, d, J=2 Hz).

Production Example 7

Production ofN-phenyl-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide(compound No. I-14)

(1) Production of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy}pyridine as an intermediate product

3.34 g (0.187×1.1 mol) of 3-(trifluoromethyl) phenol was dissolved inabout 30 ml of dimethyl formamide. The solution was further mixed with0.78 g (ca. 60% in mineral oil; 0.0187×1.04 mol) of sodium hydride andthen with 5.00 g (0.0187 mol) of 2,6-dibromo-4-methoxy pyridine. Afterstirring at about 120° C. for about 2 hours, the mixture was allowed tostand for cooling to room temperature. After the reaction solution wasdistributed with hexane-saturated sodium bicarbonate water, the organicphase of the obtained solution was washed with saturated brine and driedwith anhydrous sodium sulfate. The resultant solution was concentratedand then purified by silica gel column chromatography (eluting solution:ethyl acetate/hexane), and the obtained product was subjected torecrystallization using hexane, thereby obtaining an aimed product.

Yield by weight: 3.23 g; yield by percentage: 50%; solid; melting point:57 to 60° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 3.75 (3H, s), 6.26 (1H, d, J=2Hz), 6.75 (1H, d, J=2 Hz), 7.0-7.6 (4H, complex).

(2) Production ofN-phenyl-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide(compound No. I-14)

1.0 g (0.0029 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy}pyridine was dissolved in about 15 ml of diethyl ether. While coolingthe solution in a dry ice-acetone bath in an argon atmosphere, thesolution was mixed with 1.9 ml of about 1.69M hexane solution of BuLi(0.0029×1.1 mol), followed by stirring for about 10 minutes. After 0.86g (0.0029×2.5 mol) of phenyl isocyanate dissolved in about 5 ml ofdiethyl ether was added to the reaction solution, the bath was removedand stirred at room temperature for about 30 minutes. The reactionsolution was mixed with about 5 ml of 1.2N hydrochloric acid aqueoussolution, and then distributed with ethyl acetate-water, followed bywashing with saturated sodium bicarbonate water and saturated brine. Theorganic phase of the obtained solution was dried with anhydrous sodiumsulfate, concentrated and subjected to silica gel column chromatography(eluting solution: ethyl acetate/hexane) to separate a main fractiontherefrom. The fraction was concentrated and then subjected toprecipitation using hexane, thereby obtaining an aimed product.

Yield by weight: 0.57 g; yield by percentage: 51%; solid; melting point:140 to 142° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 3.83 (3H, s), 6.48 (1H, d,J=2 Hz), 6.8-7.7 (9H, complex), 7.52 (1H, d, J=2 Hz), 9.23 (1H, s).

Production Example 8

Production ofN-phenyl-4-methoxy-6-{3-(trifluoromethoxy)-phenoxy)}-2-pyridinecarboxamide (compound No. I-23)

(1) Production of 2-bromo-4-methoxy-6-{3-(trifluoromethoxy)phenoxy}pyridine as an intermediate product

2.00 g (0.00937×1.2 mol) of 3-(trifluoromethoxy) phenol was dissolved inabout 20 ml of dimethyl formamide. The solution was further mixed with0.39 g (ca. 60% in mineral oil; 0.00937×1.04 mol) of sodium hydride andthen with 2.50 g (0.00937 mol) of 2,6-dibromo-4-methoxy pyridine. Afterstirring at about 110° C. for about 4 hours, the mixture was allowed tostand for cooling to room temperature. After the reaction solution wasdistributed with hexane-saturated sodium bicarbonate water, the organicphase of the obtained solution was washed with saturated brine and driedwith anhydrous sodium sulfate. The resultant solution was concentratedand then purified by silica gel column chromatography (eluting solution:ethyl acetate/hexane), and the obtained product was subjected torecrystallization using hexane, thereby obtaining an aimed product.

Yield by weight: 1.40 g; yield by percentage: 41%; oily substance; ¹H-NMR (60 MHz, CDCl₃, δ): 3.73 (3H, s), 6.25 (1H, d, J=2 Hz), 6.69 (1H,d, J=2 Hz), 6.7-7.5 (4H, complex).

(2) Production ofN-phenyl-4-methoxy-6-{3-(trifluoromethoxy)phenoxy}-2-pyridinecarboxamide (compound No. I-23)

1.0 g (0.0027 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethoxy)phenoxy}pyridine was dissolved in about 15 ml of diethyl ether. While coolingthe solution in a dry ice-acetone bath in an argon atmosphere, thesolution was mixed with 2.6 ml of about 1.6M hexane solution of BuLi(0.0027×1.5 mol), followed by stirring for about 10 minutes. After 0.74g (0.0027×2.3 mol) of phenyl isocyanate dissolved in about 5 ml ofdiethyl ether was added to the reaction solution, the bath was removedand stirred at room temperature for about 45 minutes. The reactionsolution was mixed with about 5 ml of 1.2N hydrochloric acid aqueoussolution, and then distributed with ethyl acetate-saturated sodiumbicarbonate water, followed by washing with saturated brine. The organicphase of the obtained solution was dried with anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography (elutingsolution: ethyl acetate/hexane) to separate a main fraction therefrom.The fraction was concentrated and then subjected to precipitation usinghexane, thereby obtaining an aimed product.

Yield by weight: 0.74 g; yield by percentage: 67%; solid; melting point:95 to 98° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 3.82 (3H, s), 6.39 (1H, d, J=2Hz), 6.6-7.6 (9H, complex), 7.44 (1H, d, J=2 Hz), 9.19 (1H, s).

Production Example 9

Production ofN-phenyl-4-methylmercapto-6-{3-(trifluoromethyl)phenoxy}-2-pyridinecarboxamide (compound No. I-24)

(1) Production of 2,6-dibromo-4-methylmercapto pyridine as anintermediate product

A THF solution containing 3.00 g (0.0106 mol) of2,6-dibromo-4-nitropyridine was mixed with a 15% aqueous solutioncontaining 5.22 g (0.0106×1.05 mol) of sodium methyl mercaptan, and themixture was stirred at room temperature for about one hour. Further, theobtained solution was mixed with a 15% aqueous solution containing 0.5 g(0.0106×0.1 mol) of sodium methyl mercaptan and stirred at roomtemperature for about one hour. After the resultant reaction solutionwas distributed with ethyl acetate-water, the organic phase of thesolution was washed with saturated sodium bicarbonate water andsaturated brine, dried with anhydrous sodium sulfate, concentrated andthen subjected to precipitation by adding hexane thereto, therebyobtaining an aimed product.

Yield by weight: 2.64 g; yield by percentage: 88%; solid; melting point:115 to 119° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 2.42 (3H, s), 7.04 (2H, s).

(2) Production of2-bromo-4-methylmercapto-6-{3-(trifluoromethyl)phenoxy} pyridine as anintermediate product

2.06 g (0.0106×1.2 mol) of 3-(trifluoromethyl) phenol was dissolved inabout 20 ml of dimethyl formamide. The solution was further mixed with0.45 g (ca. 60% in mineral oil; 0.0106×1.06 mol) of sodium hydride andthen with 3.00 g (0.0106 mol) of 2,6-dibromo-4-methylmercapto pyridine.After stirring at about 110° C. for about 2 hours, the mixture wasallowed to stand for cooling to room temperature. After the reactionsolution was distributed with hexane-saturated sodium bicarbonate water,the organic phase of the obtained solution was washed with saturatedbrine and dried with anhydrous sodium sulfate. The resultant solutionwas concentrated and then purified by silica gel column chromatography(eluting solution: ethyl acetate/hexane), and the obtained product wassubjected to recrystallization using hexane, thereby obtaining an aimedproduct.

Yield by weight: 2.49 g; yield by percentage: 64%; solid; melting point:54 to 57° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 2.37 (3H, s), 6.50 (1H, d, J=2Hz), 6.89 (1H, d, J=2 Hz), 7.0-7.5 (4H, complex).

(3) Production ofN-phenyl-4-methylmercapto-6-{3-(trifluoromethyl)phenoxy}-2-pyridinecarboxamide (compound No. I-24)

0.8 g (0.0022 mol) of2-bromo-4-methylmercapto-6-{3-(trifluoromethyl)phenoxy} pyridine wasdissolved in about 15 ml of diethyl ether. While cooling the solution ina dry ice-acetone bath in an argon atmosphere, 1.5 ml of about 1.6Mhexane solution of BuLi (0.0022×1.1 mol) was added to the solution,followed by stirring for about 10 minutes. After 0.52 g (0.0022×2.0 mol)of phenyl isocyanate dissolved in about 5 ml of diethyl ether was addedto the reaction solution, the bath was removed and stirred at roomtemperature for about 30 minutes. The reaction solution was mixed withabout 5 ml of 1.2N hydrochloric acid aqueous solution, and thendistributed with ethyl acetate-water, followed by washing with saturatedsodium bicarbonate water and saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate, concentratedand subjected to silica gel column chromatography (eluting solution:ethyl acetate/hexane) to separate a main fraction therefrom. Thefraction was concentrated and then subjected to precipitation usinghexane, thereby obtaining an aimed product.

Yield by weight: 0.52 g; yield by percentage: 59%; solid; melting point:131 to 133° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 2.44 (3H, s), 6.76 (1H, d,J=2 Hz), 6.8-7.6 (9H, complex), 7.71 (1H, d, J=2 Hz), 9.11 (1H, s).

Production Example 10

Production ofN-phenyl-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy}-2-pyridinecarboxamide (compound No. I-25)

(1) Production of 2,6-dibromo-4-methylamino pyridine as an intermediateproduct

About 10 ml of an acetonitrile solution containing 1.00 g (0.00355 mol)of 2,6-dibromo-4-nitropyridine was mixed with a 40% aqueous solutioncontaining 1.10 g (0.00355×4.0 mol) of methyl amine, and the mixture wasstirred at room temperature for about 2 hours. After the reactionsolution was distributed with ethyl acetate-water, the organic phase ofthe obtained solution was washed with saturated sodium bicarbonate waterand saturated brine, dried with anhydrous sodium sulfate, concentratedand then subjected to precipitation by adding hexane thereto, therebyobtaining an aimed product.

Yield by weight: 0.82 g; yield by percentage: 87%; solid; melting point:189 to 193° C.; ¹ H-NMR (60 MHz, CDCl₃ +DMSO-d₆, δ): 2.70 (3H, d, J=5Hz), 6.49 (2H, s), 6.4-7.0 (1H, mult.).

(2) Production of 2,6-dibromo-4-dimethylamino pyridine as anintermediate product

2.4 g (0.0090 mol) of 2,6-dibromo-4-methylamino pyridine was added to amixed solvent containing about 30 ml of dimethyl formamide and about 40ml of diethyl ether. Further, 0.38 g (ca. 60% in mineral oil; 0.090×1.06mol) of sodium hydride was added to the solution. The solution was mixedwith 1.54 g (0.0090×1.2 mol) of methyl iodide, and stirred at roomtemperature for about one hour, followed by treating the solution underreflux for about one hour. After the reaction solution was distributedwith hexane-sodium bicarbonate water, the organic phase of the solutionwas washed with saturated brine, dried with anhydrous sodium sulfate,and concentrated. The obtained solid was washed out with hexane, therebyobtaining an aimed product.

Yield by weight: 2.39 g; yield by percentage: 95%; solid; melting point:141 to 144° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 2.91 (6H, s), 6.43 (2H, s).

(3) Production of 2-bromo-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy}pyridine as an intermediate product

1.4 g (0.0071×1.2 mol) of 3-(trifluoromethyl) phenol was dissolved inabout 20 ml of dimethyl formamide. The solution was further mixed with0.30 g (ca. 60% in mineral oil; 0.0071×1.06 mol) of sodium hydride andthen with 2.00 g (0.0071 mol) of 2,6-dibromo-4-dimethylamino pyridine.After treating the solution under reflux for about 6 hours, the solutionwas allowed to stand for cooling to room temperature. After the reactionsolution was distributed with hexane-saturated sodium bicarbonate water,the organic phase of the obtained solution was washed with saturatedbrine and dried with anhydrous sodium sulfate, followed by concentrationthereof. Thereafter, the concentrated solution was purified by silicagel column chromatography (eluting solution: ethyl acetate/hexane) andthe obtained product was subjected to recrystallization using hexane,thereby obtaining an aimed product.

Yield by weight: 1.67 g; yield by percentage: 65%; solid; melting point:61 to 66° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 2.86 (6H, s), 6.88 (1H, d, J=2Hz), 6.38 (1H, d, J=2 Hz), 6.9-7.5 (4H, complex).

(4) Production ofN-phenyl-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy}-2-pyridinecarboxamide (compound No. I-25)

0.8 g (0.0022 mol) of2-bromo-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy} pyridine wasdissolved in about 15 ml of diethyl ether. While cooling the solution ina dry ice-acetone bath in an argon atmosphere, 1.5 ml of about 1.6Mhexane solution of BuLi (0.0022×1.1 mol) was added to the solution,followed by stirring for about 10 minutes. After 0.60 g (0.0022×2.3 mol)of phenyl isocyanate dissolved in about 5 ml of diethyl ether was addedto the reaction solution, the bath was removed and stirred at roomtemperature for about 30 minutes. The reaction solution was mixed withabout 5 ml of 1.2N hydrochloric acid aqueous solution, and thendistributed with ethyl acetate-water, followed by washing with saturatedsodium bicarbonate water and saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate, concentratedand subjected to silica gel column chromatography (eluting solution:ethyl acetate/hexane) to separate a main fraction therefrom. Thefraction was concentrated and then precipitated with hexane, therebyobtaining an aimed product.

Yield by weight: 0.55 g; yield by percentage: 62%; solid; melting point:135 to 138° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 2.96 (6H, s), 6.05 (1H, d,J=2 Hz), 6.7-7.6 (10H, complex), 9.33 (1H, s).

Production Example 11

Production of N-phenyl-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine thiocarboxamide (compound No. I-26)

0.8 g (0.0023 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy}pyridine was dissolved in about 15 ml of diethyl ether. While coolingthe solution in a dry ice-acetone bath in an argon atmosphere, 1.5 ml ofabout 1.69M hexane solution of BuLi (0.0023×1.1 mol) was added thereto,followed by stirring the solution for about 10 minutes. After 0.62 g(0.0023×2.0 mol) of phenyl isothiocyanate dissolved in about 5 ml ofdiethyl ether was added to the reaction solution, the bath was removedand stirred at room temperature for about 30 minutes. The reactionsolution was mixed with about 5 ml of 1.2N aqueous hydrochloric acidsolution, and then distributed with ethyl acetate-saturated sodiumbicarbonate water, followed by washing with saturated brine. The organicphase of the obtained solution was dried with anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography (elutingsolution: ethyl acetate/hexane) to separate a main fraction therefrom.The fraction was concentrated and then precipitated with hexane, therebyobtaining an aimed product.

Yield by weight: 0.53 g; yield by percentage: 57%; solid; melting point:126 to 128° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 3.79 (3H, s), 6.43 (1H, d,J=2 Hz), 6.8-7.7 (9H, complex), 7.92 (1H, d, J=2 Hz), 11.32 (1H, s).

Production Example 12

Production ofN-phenyl-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)-phenoxy}-2-pyridinecarboxamide (compound No. I-27)

(1) Production of 4-{methyl(phenylmethyl)amino}-2,6-dibromo pyridine asan intermediate product

3.0 g (0.011 mol) of 2,6-dibromo-4-methylamino pyridine was added to amixed solvent containing about 30 ml of dimethyl formamide and about 50ml of tetrahydrofuran. The solution was further mixed with 0.47 g (ca.60% in mineral oil; 0.011×1.07 mol) of sodium hydride. The obtainedsolution was mixed with 2.32 g (0.011×1.2 mol) of benzyl bromide andstirred at room temperature for about 3 hours. After the reactionsolution was distributed with hexane-sodium bicarbonate water, theorganic phase of the solution was washed with saturated brine, driedwith anhydrous sodium sulfate, and then concentrated. The obtained solidwas washed out with hexane, thereby obtaining an aimed product.

Yield by weight: 3.0 g; yield by percentage: 75%; solid; melting point:125 to 129° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 2.92 (3H, s), 4.45 (2H, s),6.53 (2H, s), 6.7-7.4 (5H, complex).

(2) Production of2-bromo-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy}pyridine as an intermediate product

1.56 g (0.0080×1.2 mol) of 3-(trifluoromethyl) phenol was dissolved inabout 20 ml of dimethyl formamide. The solution was further mixed with0.34 g (ca. 60% in mineral oil; 0.0080×1.06 mol) of sodium hydride andthen with 2.85 g (0.0080 mol) of4-(methyl(phenylmethyl)amino)-2,6-dibromo pyridine. After treating thesolution under reflux for about 6 hours, the obtained reaction solutionwas allowed to stand for cooling to room temperature. After the reactionsolution was distributed with hexane-saturated sodium bicarbonate water,the organic phase of the obtained solution was washed with saturatedbrine and dried with anhydrous sodium sulfate. The resultant solutionwas concentrated and then purified by silica gel column chromatography(eluting solution: ethyl acetate/hexane), and the obtained eluate wassubjected to recrystallization using hexane, thereby obtaining an aimedproduct.

Yield by weight: 2.15 g; yield by percentage: 61%; solid; melting point:84 to 87° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 2.92 (3H, s), 4.38 (2H, s),5.95 (1H, d. J=2 Hz), 6.48 (1H, d, J=2 Hz), 6.7-7.6 (9H, complex).

(3) Production ofN-phenyl-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy}-2-pyridinecarboxamide (compound No. I-27)

1.00 g (0.0023 mol) of 2-bromo-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 20ml of diethyl ether. While cooling the solution in a dry ice-acetonebath in an argon atmosphere, 2.2 ml of about I.6M hexane solution ofBuLi (0.0023×1.5 mol) was added to the solution, followed by stirringfor about 10 minutes. After 0.62 g (0.0023×2.3 mol) of phenyl isocyanatedissolved in about 5 ml of diethyl ether was added to the reactionsolution, the bath was removed and stirred at room temperature for aboutone hour. The reaction solution was mixed with about 5 ml of 1.2Naqueous hydrochloric acid solution, and then distributed with ethylacetate-water, followed by washing with saturated sodium bicarbonatewater and saturated brine. The organic phase of the obtained solutionwas dried with anhydrous sodium sulfate, concentrated and subjected tosilica gel column chromatography (eluting solution: ethylacetate/hexane) to separate a main fraction therefrom. The fraction wasconcentrated and then subjected to precipitation using hexane, therebyobtaining an aimed product.

Yield by weight: 0.50 g; yield by percentage: 47%; solid; melting point:111 to 114° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 3.03 (3H, s), 4.32 (2H, s),6.09 (1H, d, J=2 Hz), 6.7-7.6 (15H, complex), 9.28 (1H, s).

Production Example 13

Production ofN-(n-propyl)-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridinecarboxamide (compound No. I-30)

0.8 g (0.0023 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy}pyridine was dissolved in about 15 ml of diethyl ether. While coolingthe solution in a dry ice-acetone bath in an argon atmosphere, 1.6 ml ofabout 1.6M hexane solution of BuLi (0.0023×1.1 mol) was added thereto,followed by stirring for about 10 minutes. After 0.39 g (0.0023×2.0 mol)of n-propyl isocyanate dissolved in about 5 ml of diethyl ether wasadded to the reaction solution, the bath was removed and stirred at roomtemperature for about one hour. The reaction solution was mixed withabout 5 ml of 1.0N aqueous hydrochloric acid solution, and thendistributed with ethyl acetate-saturated sodium bicarbonate water,followed by washing with saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate, concentratedand purified by silica gel column chromatography (eluting solution:ethyl acetate/hexane), thereby obtaining an aimed product.

Yield by weight: 0.65 g; yield by percentage: 80%; solid; melting point:60 to 64° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 0.81 (3H, t, J=7 Hz), 1.46(2H, sext, J=7 Hz), 2.9-3.6 (2H, q, J=6.4 Hz), 3.81 (3H, s), 6.41 (1H,d, J=2 Hz), 7.0-7.8 (6H, complex).

Production Example 14

Production ofN-(i-propyl)-4-methylmercapto-6-{3-(trifluoromethyl)phenoxy}-2-pyridinecarboxamide (compound No. I-37)

0.75 g (0.0021 mol) of2-bromo-4-methylmercapto-6-{3-(trifluoromethyl)phenoxy} pyridine wassuspended in about 15 ml of diethyl ether. While cooling the suspensionin a dry ice-acetone bath in an argon atmosphere, 1.4 ml of about 1.65Mhexane solution of BuLi (0.00206×1.1 mol) was added thereto, followed bystirring for about 10 minutes. After 0.35 g (0.00206×2.0 mol) ofisopropyl isocyanate dissolved in about 10 ml of diethyl ether was addedto the reaction solution, the bath was removed and stirred at roomtemperature for about one hour. The reaction solution was mixed withabout 5 ml of 1N aqueous hydrochloric acid solution, and thendistributed with ethyl acetate-saturated sodium bicarbonate water,followed by washing with saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate, concentratedand purified by using silica gel column chromatography (elutingsolution: ethyl acetate/hexane) and reversed phase column (LoborLiChroprep RP-10; eluting solution: acetonitrile/water), therebyobtaining an aimed product.

Yield by weight: 0.36 g; yield by percentage: 47%; solid; melting point:66 to 69° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 1.09 (6H, d, J=6.4 Hz), 2.50(3H, s), 3.6-4.4 (1H, mult.), 6.78 (1H, d, J=2 Hz), 6.8-7.7 (5H,complex), 7.72 (1H, d, J=2 Hz).

Production Example 15

Production ofN-(i-propyl)-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy}-2-pyridinecarboxamide (compound No. I-38)

0.75 g (0.0021 mol) of2-bromo-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy} pyridine wassuspended in about 15 ml of diethyl ether. While cooling the suspensionin a dry ice-acetone bath in an argon atmosphere, 1.4 ml of about 1.65Mhexane solution of BuLi (0.00206×1.1 mol) was added thereto, followed bystirring for about 10 minutes. After 0.35 g (0.00206×2.0 mol) ofisopropyl isocyanate dissolved in about 10 ml of diethyl ether was addedto the reaction solution, the bath was removed and stirred at roomtemperature for about one hour. The reaction solution was mixed withabout 5 ml of 1N hydrochloric acid aqueous solution, and thendistributed with ethyl acetate-saturated sodium bicarbonate water,followed by washing with saturated brine. The organic phase of theobtained solution was dried with anhydrous sodium sulfate, concentratedand purified by using silica gel column chromatography (elutingsolution: ethyl acetate/hexane) and reversed phase column (LoborLiChroprep RP-10; eluting solution: acetonitrile/water), therebyobtaining an aimed product.

Yield by weight: 0.22 g; yield by percentage: 29%; solid; melting point:108 to 110° C.; ¹ H-NMR (60 MHz, CDCl₃, δ): 1.10 (6H, d, J=6.4 Hz), 3.00(6H, s), 3.6-4.4 (1H, mult.), 6.06 (1H, d, J=2 Hz), 6.9-7.7 (6H,complex).

Production Example 16

Production ofN-(i-propyl)-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy}-2-pyridinecarboxamide (compound No. I-39) 2.22 g (0.0051 mol) of2-bromo-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy}pyridine was suspended in about 30 ml of diethyl ether. While coolingthe suspension in a dry ice-acetone bath in an argon atmosphere, 3.4 mlof about 1.65M hexane solution of BuLi (0.0051×1.1 mol) was addedthereto, followed by stirring for about 10 minutes. After 0.86 g(0.0051×2.0 mol) of isopropyl isocyanate dissolved in about 10 ml ofdiethyl ether was added to the reaction solution, the bath was removedand stirred at room temperature for about one hour. The reactionsolution was mixed with about 10 ml of 1N hydrochloric acid aqueoussolution, and then distributed with ethyl acetate-saturated sodiumbicarbonate water, followed by washing with saturated brine. The organicphase of the obtained solution was dried with anhydrous sodium sulfate,concentrated and purified by silica gel column chromatography (elutingsolution: ethyl acetate/hexane), thereby obtaining an aimed product.

Yield by weight: 1.24 g; yield by percentage: 55%; oily substance; ¹H-NMR (60 MHz, CDCl₃, δ): 1.09 (6H, d, J=6.4 Hz), 3.06 (6H, s), 3.6-4.4(1H, mult.), 4.52 (2H, s), 6.09 (1H, d, J=2 Hz), 6.8-7.6 (11H, complex).

Various compounds (I) were produced by the processes according to theabove-mentioned Production Examples 1 to 16. The obtained compoundsaccording to the present invention are shown in Tables 2 to 7 below.

                  TABLE 2                                                         ______________________________________                                        Substituents                                                                  Compound                                                                              Z      A.sup.b)             Yield                                                                              Property                               No. W.sup.a) X.sub.n.sup.b) R.sub.m.sup.c) Y.sub.p.sup.d) (%) (m.p.                                                  ° C.)                         ______________________________________                                        I-1     O      CHCH3   --      --   27   Solid                                   4 1-CH3    (105-107)                                                         I-2 O CHCH3 6-Br -- 78 Oily                                                    2 1-CH3    substance                                                         I-3 O CHCH3 4-CH3 -- 82 Oily                                                   2 1-CH3    substance                                                         I-4 O CHCH3 4-Cl -- 39 Solid                                                   3 1-CH3    (96-98)                                                           I-5 O Ph 4-OCH3 -- 70 Solid                                                    2 -- 6-Br   (145-147)                                                        I-6 O Ph 4-SCH3 -- 51 Solid                                                    2 4-CH3 6-Br   (145-149)                                                     I-7 O Ph 4-OCH3 -- 57 Solid                                                    2 4-CH3 6-Br   (153-157)                                                     I-8 O Ph 4-OCH2CH3 -- 80 Solid                                                 2 -- 6-Br   (91-95)                                                          I-9 O CH2Ph 4-OCH3 -- 86 Solid                                                 2  6-Br   (107-111)                                                        ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________           Substituents              Property                                     Compound No.                                                                         Z W.sup.a)                                                                       A.sup.b) X.sub.n.sup.b)                                                                R.sub.m.sup.c)                                                                     Y.sub.p.sup.d)                                                                    Yield (%)                                                                          (m.p. ° C.)                           __________________________________________________________________________    I-10   O  CHCH3    4-OCH3                                                                             --  74   Solid                                           2 1-CH3 6-Br   (70-76)                                                       I-11 O CH2CH2CH2CH3 4-OCH3 -- 82 Solid                                         2 -- 6-Br   (44-48)                                                          I-12 O CH2CH2CH3 4-OCH3 -- 70 Oily                                             2 -- 6-Br   substance                                                        I-13 S CH2CH3 4-OCH3 -- 68 Solid                                               2 -- 6-Br   (59-62)                                                          I-14 O Ph 4-OCH3 3-CF3 51 Solid                                                2 -- 6-OPh   (140-142)                                                       I-15 O Ph 4-OCH3 3-CF3 56 Solid                                                2 4-Cl 6-OPh   (120-122)                                                     I-16 O Ph 4-OCH3 3-CF3 57 Solid                                                2 3-CH3 6-OPh   (145-146)                                                    I-17 O Ph 4-OCH3 3-CF3 46 Solid                                                2 4-OCH3 6-OPh   (148-149)                                                   I-18 O Ph 4-OCH3 3-CF3 40 Solid                                                2 4-SCH3 6-OPh   (115-116)                                                 __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________            Substituents             Property                                     Compound No.                                                                          Z W.sup.a)                                                                       A.sup.b) X.sub.n.sup.b)                                                           R.sub.m.sup.c)                                                                        Y.sub.p.sup.d)                                                                     Yield (%)                                                                          (m.p. ° C.)                           __________________________________________________________________________    I-19    O  Ph  4-OCH3  3-CF3                                                                              60   Solid                                           2 3-CF3 6-OPh   (135-137)                                                    I-20 O Ph 4-OCH3 3-CF3 55 Solid                                                2 4-F 6-OPh   (133-135)                                                      I-21 O Ph 4-OCH3 3-CF3 52 Solid                                                2 2,4-F2 6-OPh   (135-137)                                                   I-22 S Ph 4-OCH3 3-OCHF2 42 Solid                                              2 -- 6-OPh   (101-104)                                                       I-23 O Ph 4-OCH3 3-OCF3 67 Solid                                               2 -- 6-OPh   (95-98)                                                         I-24 O Ph 4-SCH3 3-CF3 59 Solid                                                2 -- 6-OPh   (131-133)                                                       I-25 O Ph 4-N(CH3)2 3-CF3 62 Solid                                             2 -- 6-OPh   (135-138)                                                       I-26 S Ph 4-OCH3 3-CF3 57 Solid                                                2 -- 6-OPh   (126-128)                                                       I-27 O Ph 4-N(CH3)CH2Ph 3-CF3 47 Solid                                         2 -- 6-OPh   (111-114)                                                     __________________________________________________________________________

                  TABLE 5                                                         ______________________________________                                        Comp- Substituents                                                            ound  Z      A.sup.b)               Yield                                                                              Property                               No. W.sup.a) X.sub.n.sup.b) R.sub.m.sup.c) Y.sub.p.sup.d) (%) (m.p.                                                  ° C.)                         ______________________________________                                        I-28  S      Ph        4-OCH3 3-CF3 38   Solid                                   2 4-Cl 6-OPh   (130-132)                                                     I-29 O Ph 4-OCH3 3-CF3 27 Solid                                                2 4-Br 6-OPh   (103-108)                                                     I-30 O (CH2)2CH3 4-OCH3 3-CF3 80 Solid                                         2 -- 6-OPh   (60-64)                                                         I-31 S (CH2)2CH3 4-OCH3 3-CF3 76 Solid                                         2 -- 6-OPh   (91-93)                                                         I-32 O CH2CH2 4-OCH3 3-CF3 52 Solid                                            2 2-Cl 6-OPh   (64-68)                                                       I-33 O CCH3 4-OCH3 3-CF3 80 Solid                                              2 1,1-(CH3)2 6-OPh   (110-115)                                             ______________________________________                                    

                                      TABLE 6                                     __________________________________________________________________________            Substituents               Property                                   Compound No.                                                                          Z W.sup.a)                                                                       A.sup.b) X.sub.n.sup.b)                                                              R.sub.m.sup.c)                                                                        Y.sub.p.sup.d)                                                                    Yield (%)                                                                          (m.p. ° C.)                         __________________________________________________________________________    I-34    O  CH2CH=CH2                                                                            4-OCH3  3-CF3                                                                             73   Oily                                          2 -- 6-OPh   substance                                                       I-35 O cyclohexyl 4-OCH3 3-CF3 63 Solid                                        2 -- 6-OPh   (111-115)                                                       I-36 S CH2CH3 4-OCH3 3-CF3 61 Solid                                            2 -- 6-OPh   (112-116)                                                       I-37 O CHCH3 4-SCH3 3-CF3 47 Solid                                             2 1-CH3 6-OPh   (66-69)                                                      I-38 O CHCH3 4-N(CH3)2 3-CF3 29 Solid                                          2 1-CH3 6-OPh   (108-110)                                                    I-39 O CHCH3 4-N(CH3)CH2Ph 3-CF3 55 Oily                                       2 1-CH3 6-OPh   substance                                                    I-40 O CH3 4-OCH2CH3 3-CF3 43 Solid                                            2 -- 6-OPh   (65-67)                                                       __________________________________________________________________________

                  TABLE 7                                                         ______________________________________                                        Comp- Substituents                                                            ound  Z      A.sup.b)               Yield                                                                              Property                               No. W.sup.a) X.sub.n.sup.b) R.sub.m.sup.c) Y.sub.p.sup.d) (%) (m.p.                                                  ° C.)                         ______________________________________                                        I-41  O      CHCH3    4-OCH2CH3                                                                             3-CF3 55   Solid                                   2 1-CH3 6-OPh   (66-68)                                                      I-42 O CH2CH3 4-OCH3 3-CF3 74 Solid                                            2 -- 6-OPh   (81-82)                                                         I-43 O CH3 4-OCH3 3-CF3 56 Solid                                               2 -- 6-OPh   (123-125)                                                       I-44 S CH3 4-OCH3 3-CF3 69 Solid                                               2 -- 6-OPh   (124-127)                                                     ______________________________________                                         Note of Tables 2 to 7.                                                        .sup.a) : Each number represents a bonding position where the carboxamide     or thiocarboxamide moiety of each compound is bonded to the pyridine ring     .sup.b) : The symbol "Ph" represents a phenyl group.                     

In the case where A has substituents thereon, the number prefixed to theen dash (-) represents a bonding position of each substituent, and thenumber suffixed to the en dash (-) represents the number of bondingpositions when the same kind of 2 or more substituents are present.

"4-Cl" of the compound (I-15) indicates that one Cl (chloro) is bondedto the 4-position of phenyl ring, and "2,4-F2" of the compound (I-21)indicates that "F"s (fluoro) are bonded to two positions, i.e., the 2-and 4-positions of phenyl ring.

"CH2CH2" of the compound (I-32) indicates that one of carbon atoms ofCH₂ CH₂ which is unsaturated with respect to bonding number, is bondedto a nitrogen atom of 2-CONH of pyridine, and the other carbon atom isbonded to X_(n), and "2-Cl" indicates that Cl is bonded to the2-position carbon atom, assuming that the carbon atom of CH₂ CH₂ whichis bonded to the nitrogen atom of 2-CONH of pyridine, is in the1-position.

"CCH3" of the compound (I-33) indicates that the carbon atom which isunsaturated in bonding number, is bonded to the nitrogen atom of 2-CONHof pyridine, and the same carbon atom is also bonded to X_(n)."1,1-(CH3)2" of the compound (I-33) indicates that two CH₃ groups arebonded to the above-mentioned carbon atom. Thus, in the case where A isrepresented by only carbon atoms and hydrogen atoms, the carbon atombonded to the nitrogen atom of 2-CONH of pyridine or X_(n) is indicatedin such a condition as unsaturated with respect to bonding numberthereof.

The em dash (--) means an unsubstituted condition (n=0).

c): With respect to R, the number prefixed to the en dash (-) representsa bonding position thereof.

d): Yp represents a substituent bonded to the benzene ring in the casewhere R is a phenoxy group. The regularities of Y_(p) are the same asthose of X_(n) in the case of A=Ph.

INDUSTRIAL APPLICABILITY

As described above, the process for the production of N-substitutedpyridine carboxamide or thiocarboxamide according to the presentinvention can be applied even to such compounds havingoxidation-susceptible substituent groups, and it is not necessary toproduce substituted or unsubstituted pyridine thiocarboxamide fromcorresponding substituted or unsubstituted pyridine carboxamide.Therefore, the process of the present invention is industrially useful.

What is claimed is:
 1. A process for producingN-substituted-(substituted or unsubstituted) pyridine carboxamide orthiocarboxamide, comprising reacting a substituted or unsubstitutedpyridine metal compound with substituted isocyanate or thioisocyanate toobtain an addition reaction product thereof, and then substituting themetal of said addition reaction product with a proton.
 2. A processaccording to claim 1, wherein N-substituted pyridine carboxamide orthiocarboxamide represented by the general formula (I) is produced byreacting a pyridine metal compound represented by the general formula(II) with substituted isocyanate or isothiocyanate to obtain an additionreaction product thereof, and then substituting the metal of saidaddition reaction product with a proton, ##STR4## wherein R is ahydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, analkoxy group, a haloalkoxy group, an alkylthio group, a haloalkylthiogroup, a dialkylamino group, a (substituted or unsubstituted) phenoxygroup, a (substituted or unsubstituted) phenylthio group, adi{(substituted or unsubstituted)phenyl}amino group, analkyl{(substituted or unsubstituted)phenyl}amino group, analkyl{(substituted or unsubstituted)phenylalkyl}amino group or a{(substituted or unsubstituted)phenyl} {{substituted orunsubstituted)phenyl}alkyl}amino group;m is an integer of 0 to 4, andwhen m is an integer of not less than 2, Rs may be the same ordifferent; A is an alkyl group, an alkenyl group, an alkynyl group, acycloalkyl group, a cycloalkylalkyl group, a phenyl group or an aralkylgroup; X is a halogen atom, an alkoxy group, a haloalkoxy group, analkylthio group, an alkyl group, a haloalkyl group or a di(alkyl)aminogroup; n is 0 to an integer selected from numbers of hydrogen atomswhich can be substituted with hydrocarbon groups, and when n is aninteger of not less than 2, Xs may be the same or different; Z is anoxygen atom or a sulfur atom; and M is alkali metal, alkali earthmetal-Q wherein Q is a halogen atom, or 1/2(Cu-alkali metal).
 3. Aprocess according to claim 1, wherein said metal is lithium.